JP2020109125A - Ophthalmic composition - Google Patents

Abstract

To provide an ophthalmic composition which can alleviate a stimulus to an eye.SOLUTION: The present invention provides an ophthalmic composition comprising polysorbate 80 and a refreshing agent, where a polydispersity (Mz/Mw) of the polysorbate 80 in the ophthalmic composition is 1.27-1.63.SELECTED DRAWING: None

Description

The present invention relates to ophthalmic compositions.

The cornea is a tissue formed on the outermost surface of the eyeball. The perception of the cornea is considered to be one of the most sensitive perceptions of human pain. Therefore, the cornea sensitively perceives the influence of external factors such as dryness or bacterial infection, and internal factors such as a change in the composition of tear fluid. In addition, a component contained in an ophthalmic composition used for treating or ameliorating various symptoms of the eye may cause irritation to the eye as one of external factors. Therefore, it is required that the ophthalmic composition not only improve each symptom but also do not cause pain or load to the user. An ophthalmic composition containing dextran, menthol and a surfactant has been found as a measure against the sensation of sensation caused by polysorbate 80 or a cooling agent (Patent Document 1). However, no influence on the specific properties of polysorbate 80 has been reported so far.

Japanese Patent Laid-Open No. 2009-046480

It has been known that polysorbate 80 or a refreshing ingredient (such as a refreshing agent) may have various effects on eyes such as irritation. In other words, controlling the influence on the surface of the eyeball is important from the viewpoint of eliminating unspecified complaints and improving the quality of life.
The present invention has been made in view of the above circumstances, and an object thereof is to provide an ophthalmic composition capable of relieving irritation to the eye.

The present inventors have conducted extensive studies to solve the above-mentioned problems, and as a result, when polysorbate 80 having a relatively high polydispersity in an ophthalmic composition and a cooling agent coexist, the adsorption rate to phospholipids is suppressed. It was newly confirmed that it will be done. That is, an ophthalmic composition containing (A) polysorbate 80 (hereinafter sometimes referred to as “(A) component”) and (B) cooling agent (hereinafter sometimes referred to as “(B) component”). It was found that an ophthalmic composition having a polydispersity of the component (A) in the ophthalmic composition of 1.27 to 1.63 suppresses the adsorption rate to phospholipids. The present inventors are the first to pay attention to the polydispersity of polysorbate 80 in an ophthalmic composition with regard to the influence on the adsorption rate to phospholipids. As a result of further investigations by the present inventors, the present inventors also found that the ophthalmic composition having the above-mentioned constitution can maintain the aromaticity in the ophthalmic composition and can suppress the deterioration of the contact lens. The present inventors have completed the present invention based on these findings.

That is, the present invention provides the following ophthalmic compositions. Although details such as the control mechanism of the adsorption rate to phospholipids by setting the polydispersity of polysorbate 80 to the following range have not been clarified, due to the difference in polydispersity, the micelle structure of polysorbate 80 and the cooling agent is Is slightly different, which may be one of the reasons that it affects the affinity with phospholipids. It is considered that the affinity of phospholipid affects the adsorbability of components in the composition to cells and may be involved in the sensation of stimulation.

That is, the present invention provides the following [1] to [10].
[1] Polysorbate 80,
A cooling agent,
An ophthalmic composition containing:
An ophthalmic composition, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity index (M _z /M _w ) of 1.27 to 1.63.
[2] The above [1] further containing at least one selected from the group consisting of polyvinyl alcohol, glycerin, panthenol, sulfamethoxazole and salts thereof, calcium chloride, magnesium sulfate, sodium hydrogen carbonate, and mannitol. ] The ophthalmic composition according to.
[3] The total content of the cooling agent is 0.0001 to 100 parts by mass with respect to the content of 1 part by mass of the polysorbate 80 contained in the ophthalmic composition, and the above [1] or [2]. ] The ophthalmic composition according to.
[4] The ophthalmic composition according to any one of the above [1] to [3], which has a pH of 4.0 to 9.5.
[5] An adsorption rate inhibitor for ocular cells, comprising polysorbate 80 and a cooling agent,
An adsorption rate inhibitor for ocular cells, wherein the polysorbate 80 in the adsorption rate inhibitor has a polydispersity (M _z /M _w ) of 1.27 to 1.63.
[6] An aromatic lasting agent for an ophthalmic composition, comprising polysorbate 80 and a cooling agent, wherein the polydispersity (M _z /M _w ) of the polysorbate 80 in the aromatic lasting agent is Fragrance lasting agent, 1.27 to 1.63.
[7] A deterioration inhibitor for a soft contact lens, comprising polysorbate 80 and a cooling agent, wherein the polydisperse 80 in the deterioration inhibitor for a soft contact lens has a polydispersity of 1.27 to 1. 63, a deterioration inhibitor for soft contact lenses.
[8] A method for imparting an adsorption rate suppressing action to phospholipids to the ophthalmic composition, which comprises adding polysorbate 80 and a cooling agent to the ophthalmic composition,
The method wherein the polysorbate 80 in the ophthalmic composition has a polydispersity index (M _z /M _w ) of 1.27 to 1.63.
[9] A method for imparting to the above-mentioned ophthalmic composition an action of maintaining the fragrance of the above-mentioned refreshing agent, which comprises adding polysorbate 80 and a refreshing agent to the ophthalmic composition,
The method wherein the polysorbate 80 in the ophthalmic composition has a polydispersity index (M _z /M _w ) of 1.27 to 1.63.
[10] A method for imparting an action of suppressing alteration of a soft contact lens to the ophthalmic composition, which comprises adding polysorbate 80 and a cooling agent to the ophthalmic composition.
The method wherein the polysorbate 80 in the ophthalmic composition has a polydispersity index (M _z /M _w ) of 1.27 to 1.63.

According to the present invention, it becomes possible to provide an ophthalmic composition capable of relieving eye irritation.
Further, according to the present invention, it becomes possible to provide an ophthalmic composition capable of controlling the adsorption rate to phospholipids. Specifically, it becomes possible to provide an ophthalmic composition that suppresses the adsorption rate of polysorbate 80 or a cooling agent to phospholipids and reduces irritation or toxicity to eye cells.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments. In the present specification, the unit of content “%” means “w/v%” and has the same meaning as “g/100 mL”.

In the present specification, the irritation to the eyes includes not only eye disorders but also subjective symptoms of the eyes caused by dryness of the eyes, use of contact lenses, or allergic conjunctivitis, as well as subjective symptoms of the eyes. Therefore, the present inventors have focused on controlling the adsorption rate to eye cells and improving subjective symptoms themselves in order to reduce irritation or discomfort to the eyes. In particular, suppressing the adsorption rate of the component (A) or the component (B) exhibits an effect of suppressing damage or discomfort to eye cells.

The ophthalmic composition according to the present embodiment (hereinafter, may be simply referred to as “ophthalmic composition”) contains (A) polysorbate 80 and (B) a cooling agent, and is contained in the ophthalmic composition. The polydispersity of the polysorbate 80 is 1.27 to 1.63.

(Ophthalmic composition)
Component (A) The polysorbate 80 according to the present embodiment (hereinafter sometimes simply referred to as “polysorbate 80”) is not particularly limited as long as the polydispersity is 1.27 to 1.63. The polysorbate 80 can be obtained by measuring the commercially available polysorbate 80 by the measuring method described below and selecting the polysorbate 80 having a polydispersity of 1.27 to 1.63.

Alternatively, polysorbate 80 obtained as a commercial product can be further fractionated or purified by a known method to obtain polysorbate 80 having a polydispersity of 1.27 to 1.63. The method for fractionating or purifying the polysorbate 80 is not particularly limited, but is a purification treatment using an ion exchange resin, activated carbon or an adsorbent, steam deodorization treatment, decolorization treatment, dehydration desolvation, filter filtration, cake filtration, centrifugation, sedimentation. A method such as removal or a method in which two or more kinds of these are combined can be used. These fractionation or purification methods can be carried out if it is necessary to eliminate adverse effects on the measurement error of polydispersity and the like. Other fractionation methods of the polysorbate 80 include, for example, membrane filtration, distillation, organic solvent extraction or washing, reprecipitation, liquid/liquid separation, and the like, or two or more of these. A combination method can be mentioned. Specific examples include the following membrane filtration methods. The molecular weight and polydispersity of the polysorbate 80 obtained as a commercial product are measured by the size exclusion chromatography (SEC) method described later, and an appropriate ultrafiltration membrane having a rejection rate close to 90% and a permeation flux is obtained is selected. .. As the filtration membrane, a commercially available one can be used (for example, UF disk PLBC Ultracell RC 3K NMWL (molecular weight cutoff 3 KDa, cellulose membrane) (manufactured by Millipore Corporation)). A pressure of 0.5 to 200 Pa is applied according to the limit pressure of the filtration membrane. Polysorbate 80 having a polydispersity of 1.27 to 1.63 can be obtained by fractionation based on the weight average molecular weight and the Z average molecular weight.
Other methods of refining the polysorbate 80 include, for example, crystallization, resin chromatography, a method in which the reaction solution is dried by a spray dryer and powderized, a method in which steam distillation is performed to remove, and an organic solvent and water. Liquid-liquid extraction method and the like can be mentioned. Specific examples of the purification method include the following methods. First, polysorbate 80 is dissolved in methanol and the molecular weight at the critical micelle concentration is measured by the light scattering method to determine the molecular weight cutoff of the ultrafiltration membrane. Next, membrane filtration is performed under the conditions of a flow rate of 0.5 to 10 ml/min and a pressure of 0.1 to 20 bar.

Alternatively, although the method for producing the polysorbate 80 is not particularly limited, the polysorbate 80 having a polydispersity of 1.27 to 1.63 can be obtained by the following method. It is produced by adding ethylene oxide to a mixture obtained by partially esterifying sorbitol and/or anhydrous sorbitol with a fatty acid mainly composed of oleic acid. The ester reaction can be carried out with sorbitan and a fatty acid under a basic catalyst, under an inert gas stream, under normal pressure or reduced pressure, usually at a temperature of 150 to 280°C. After the reaction, a small amount of acid sufficient to deactivate the basic catalyst is added for neutralization. The raw material sorbitol can be obtained by high-pressure hydrogen reduction of glucose, or a commercially available sorbitol may be used (for example, sorbit D-70 (manufactured by Towa Kasei Co., Ltd.), sorbitol S (Japan). Ken Kagaku Co., Ltd.) and the like.). Sorbitan can be obtained by subjecting sorbitol to cyclodehydration, or a commercially available product may be used (for example, manufactured by Toei Chemical Co., Ltd., etc.). Alternatively, a commercially available sorbitan oleic acid ester can be used. The step of adding ethylene oxide to the sorbitan fatty acid ester uses a catalyst such as an alkali metal catalyst and fatty acid soaps. The produced polysorbate 80 can be filtered. The basic catalyst in the ester reaction is an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide, an alkali metal carbonate such as sodium carbonate and potassium carbonate, an alkali metal hydrogen carbonate, an alkali metal, Alkaline earth metals, alkaline earth metal oxides, alkaline earth metal hydroxides, other metals, oxides thereof, and alkaline compounds such as mixtures thereof, and phosphorous acid (salt) and/or hypochlorous acid It is used in combination with phosphoric acid (salt). The inert gas used may be nitrogen or argon, for example. Examples of the metal catalyst for adding ethylene oxide to the product after the ester reaction include potassium hydroxide, sodium hydroxide, sodium methylate and the like. By further fractionating or purifying the polysorbate 80 thus obtained by a known method, polysorbate 80 having a polydispersity of 1.27 to 1.63 can be obtained.

Furthermore, a polysorbate 80 having a polydispersity of 1.27 to 1.63 can be prepared by mixing two or more kinds of polysorbate 80 having different polydispersities.

The ophthalmic composition according to the present embodiment has a polydispersity of 1.27 to 1.63, which is a commercially available product, and a polydispersity of 1. A polysorbate 80 of 27 to 1.63, or a polysorbate 80 having a polydispersity of 1.27 to 1.63 produced by the above production method, and a cooling agent Good. Moreover, you may manufacture by the method including the process of mix|blending two or more types of polysorbate 80 obtained by the different method, and a cooling agent. The polydispersity of the polysorbate 80 in the ophthalmic composition can be 1.27 to 1.63 by being produced by such a method.

The polydispersity of the polysorbate 80 is 1.27 to 1.63, preferably 1.29 to 1.63, more preferably 1.34 to 1.63, and 1.27 to 1 It is even more preferably 0.50 and even more preferably 1.29 to 1.50. By setting the polydispersity to such a range, the effect of the present invention of controlling the adsorption rate to the eye cells or alleviating the discomfort of the eye can be more remarkably exhibited.

The weight average molecular weight of the polysorbate 80 is not particularly limited, but is preferably 1200 to 3200, more preferably 1300 to 3000. The Z average molecular weight of the polysorbate 80 is not particularly limited, but is preferably in the range of 1300 to 3500, more preferably 1400 to 3300.
By controlling the weight average molecular weight and the Z average molecular weight of the polysorbate 80 within the above ranges, the effect of the present invention of controlling the adsorption rate to eye cells or alleviating the discomfort of the eye can be more remarkably exhibited.
The methods for measuring and calculating the weight average molecular weight, Z average molecular weight, and polydispersity are as described below.

The polydispersity of polysorbate 80 is defined as M _z /M _w . M _z indicates a Z average molecular weight, and M _w indicates a weight average molecular weight.

Various molecular weight measuring methods such as liquid chromatography, ultracentrifugation method, light scattering method and intrinsic viscosity method are known as molecular weight measuring methods. The kind of the obtained average molecular weight such as the weight average molecular weight and the Z average molecular weight or the measurable molecular weight range varies depending on the difference in the measuring method. The weight average molecular weight, Z average molecular weight and polydispersity degree defined in the present invention are measured by the size exclusion chromatography (SEC) method. The SEC method can measure the weight average molecular weight, the Z average molecular weight, and the polydispersity, and is easy to operate.

The SEC method uses a gel-filled column having pores as a packing material, and has a mechanism of separation due to a difference in the migration distance depending on the molecular size in the sample solution and the elution time being different. Average molecular weights such as M _z and M _w are calculated based on a calibration curve prepared by using standard substances having known molecular weights. As described above, the Z-average molecular weight, the weight-average molecular weight and the polydispersity index obtained by the SEC method are relative values obtained by calibrating the molecular weight using the standard substance. Therefore, it is possible to use the same standard substance. Only obtained. Therefore, the SEC method of the present invention is defined as using polyethylene oxide and polyethylene glycol as standard substances, as described later. Further, since it is a relative value, it is also important to set the conditions in the separation of the test component and the preparation of the calibration curve. In view of these characteristics of the SEC method, the inventors diligently studied the measurement conditions of the SEC method in order to improve the accuracy of calculation of the Z average molecular weight, the weight average molecular weight, and the polydispersity of polysorbate 80.

In the present embodiment, the weight average molecular weight, Z average molecular weight and polydispersity of polysorbate 80 in the ophthalmic composition are measured as follows.
(Preparation of calibration curve solution)
1. Polyethylene oxide (Tosoh Corporation) and polyethylene glycol (Wako Pure Chemical Industries, Ltd.) having a molecular weight of hundreds of thousands to hundreds are used as standard substances. Polyethylene oxide and polyethylene glycol as standard substances have molecular weights of several hundred thousand, three types, molecular weights of tens of thousands, two of which molecular weights are of several thousands, and molecular weights of several hundreds. It is preferable to use one kind. More preferably, polyethylene oxide having a molecular weight of 580000, 255000, 146000, 44900, 27000 and polyethylene glycol having a molecular weight of 8000, 1000, 600 are used and divided into molecular weights of 580000, 146000, 27000, 1000 and 255,000, 44900, 8000, 600. , Combine so that the elution positions do not overlap.
2. An aqueous solution having a concentration of the standard substance of 0.1 w/v% is prepared and used as a standard solution. Setting the concentration of the standard substance to 0.1 w/v% is very important for suppressing the relative standard deviations of the Z average molecular weight, the weight average molecular weight, and the polydispersity index.
3. Accurately take 1.0 mL of the standard solution, and add exactly 4.0 mL of methanol to obtain a solution of the calibration curve.
(Preparation of sample solution)
4. Accurately take 1.0 mL of the test solution, and add exactly 4.0 mL of methanol as the sample solution.
(Measurement by liquid chromatography)
5. Each calibration curve solution and sample solution are measured by a high performance liquid chromatograph (Agilent 1200 series, manufactured by Agilent Technologies).
6. The column is manufactured by Tosoh Corporation, and TSK-Gel α-4000 (exclusion limit molecular weight of about 400,000) and TSK-Gel α-2500 (exclusion limit molecular weight of about 5000) filled with a hydrophilic vinyl polymer (both columns have an inner diameter of 7.8 mm). , 300 mm in length) are installed one by one in this order. The column temperature is 40.0°C. Keeping 40.0° C. constant is very important for suppressing the relative standard deviations of Z-average molecular weight, weight-average molecular weight and polydispersity.
7. As the eluent, a mixed solution in which the volume of methanol is 4.0 times that of a 0.10 mol/L sodium chloride aqueous solution is prepared and used for each measurement. Including sodium chloride in the eluent to suppress the interaction between sample molecules or between the sample molecules and the packing material is very important for suppressing the relative standard deviations of Z-average molecular weight, weight-average molecular weight, and polydispersity. Is.
8. The flow rate is 0.5 mL/min.
9. The injection volume is 50 μL. Filter by 0.45 μm filter before injection.
10. The calibration curve solution and the sample solution are measured in this order, and the analysis cycle is 60 minutes for the calibration curve solution and 90 minutes for the sample solution. Continuous measurement of the calibration curve solution and the sample solution without interrupting the measurement is very important for suppressing the relative standard deviations of the Z-average molecular weight, the weight-average molecular weight, and the polydispersity.
11. The detector is a differential refractive index detector, and the detector temperature is 35.0°C.
(Calculation of Z-average molecular weight, weight-average molecular weight and polydispersity)
12. The obtained chromatogram is analyzed by an SEC analyzer, and the Z-average molecular weight and the weight-average molecular weight are calculated for the range between the chromatogram curve and the baseline. The elution time and the molecular weight value of each peak are plotted from the solution of the calibration curve and approximated by a linear equation to obtain a calibration curve, and the correlation coefficient is 0.99 or more. Furthermore, in order to reduce the error in the analytical processing of the chromatogram, the obtained peak is vertically divided at intervals of 0.1 minute or more and less than 0.001 minute to calculate the average molecular weight.
13. The polydispersity is calculated from the formula of M _z /M _w . Above 4. The sample solution of the process shown in step 3 is measured three times, and the average value of the Z-average molecular weight, the weight-average molecular weight or the polydispersity determined respectively is adopted as the Z-average molecular weight, the weight-average molecular weight or the polydispersity of the present application. To do.

The relative standard deviation of the average molecular weight in the generally known SEC method is calculated by the following formula A and formula B and is about 4-5%. Since the relative standard deviation of polydispersity is less than 5% under the above-mentioned SEC measurement conditions, it can be said that the measurement conditions are appropriate. The polydispersity in the present application is measured and calculated so that the relative standard deviation is less than 5%. When the above-mentioned reagents, columns, liquid chromatographs, etc. are not available, it is possible to carry out the measurement by using substitutes equivalent to these. However, it is necessary to measure so that the relative standard deviation of polydispersity is less than 5%. When the relative standard deviation is 5% or more, it is necessary to suppress the relative standard deviation within the range of study of the measurement conditions that are usually performed. In order to suppress the relative standard deviation in the study by the present inventors, it is important to satisfy the above conditions with respect to the concentration of the standard substance, the column temperature, the composition of the eluent, and the analysis cycle of the calibration curve solution and the sample solution. It was

The content of the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type and content of the component (B) used in combination. The content of the component (A) is, for example, preferably 0.0001 to 8 w/v%, more preferably 0.0001 to 4 w/v%, based on the total amount of the ophthalmic composition. It is more preferably 0.0005 to 2 w/v%, and particularly preferably 0.001 to 1 w/v%. The content of the above-mentioned component (A) is suitable from the viewpoint of the effect of controlling the adsorption rate to eye cells or relieving the discomfort of the eye.

Component (B) The component (B) is a cooling agent. As the component (B), one type may be used alone, or two or more types may be used in arbitrary combination.

The cooling agent used in the ophthalmic composition according to the present embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of the cooling agent include terpenoids and essential oils containing terpenoids (for example, eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, spearmint oil, camphor oil, coolmint and mint oil) and the like. Can be mentioned. Examples of the terpenoid include menthol, menthone, camphor (also referred to as “camphor” or “camphor”), borneol (also referred to as “ryuuno” or “dragon brain”), geraniol, nerol, cineol, citronellol, carvone, anethole, Examples include eugenol, limonene, linalool and linalyl acetate. The terpenoid may be any of d-form, l-form and dl-form, and examples thereof include l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol and d-borneol. However, some terpenoids such as geraniol, nerol, and cineol may not have optical isomers. From the viewpoint of the effect of controlling the rate of adsorption to eye cells or alleviating the discomfort of the eye, the cooling agent preferably contains at least one selected from the group consisting of menthol, camphor, borneol and geraniol. It is particularly preferable to include at least one selected from the group consisting of 1-menthol, dl-camphor, d-camphor and d-borneol.

The content of the cooling agent in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of the cooling agent, the type and content of the component (A) used in combination, and the like. The content of the cooling agent can be measured as a terpenoid. For example, the total content of the cooling agent (as a terpenoid) is 0.00005 to 0.5 w/v based on the total amount of the ophthalmic composition. %, more preferably 0.0001 to 0.3 w/v%, further preferably 0.0005 to 0.2 w/v%, and 0.001 to 0.1 w/v. % Is particularly preferable. The content of the above-mentioned cooling agent is suitable from the viewpoint of the effect of controlling the adsorption rate to eye cells or relieving the discomfort of the eye.

The content ratio of the cooling agent to the component (A) in the ophthalmic composition according to the present embodiment is not particularly limited, and is appropriately set according to the type of the cooling agent and the like. As the content ratio of the cooling agent to the component (A), for example, the total content of the cooling agent is 0.0001 to 100 relative to 1 part by mass of the content of the component (A) contained in the ophthalmic composition. It is preferably mass part, more preferably 0.001 to 80 mass part, still more preferably 0.005 to 60 mass part, and particularly preferably 0.01 to 50 mass part. The content ratio of the cooling agent to the component (A) is suitable from the viewpoint of the effect of controlling the adsorption rate to eye cells or alleviating the discomfort of the eye.

Component (C) The ophthalmic composition according to the present embodiment may further include the component (C) described below. Component (C) is selected from the group consisting of polyvinyl alcohol (fully saponified or partially saponified), glycerin, panthenol, sulfamethoxazole and its salts, calcium chloride, magnesium sulfate, sodium hydrogen carbonate, and mannitol. It is at least one kind. As the component (C), one type may be used alone, or two or more types may be used in arbitrary combination. By using the component (C) in combination, the effects of the present invention can be exhibited more significantly. Particularly, by using the component (C) together, the aroma of the cooling agent contained in the ophthalmic composition can be further maintained. The details of the mechanism of controlling the adsorption rate to phospholipids by using the component (C) together have not been clarified, but by using the component (C) together, the micelle structure of the polysorbate 80 and the cooling agent is improved. It is also considered that it is slightly different and affects the affinity with phospholipids.

The component (C) used in the ophthalmic composition according to this embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

The content of the component (C) used in the ophthalmic composition according to the present embodiment is not particularly limited, and depends on the type of the component (C), the types and contents of the component (A) and the component (B) used in combination, and the like. Is set appropriately. The content of the component (C) is, for example, preferably 0.00005 to 10 w/v%, and more preferably 0.0001 to 8 w/v%, based on the total amount of the ophthalmic composition. It is more preferably 0.0005 to 6 w/v%, further preferably 0.001 to 5 w/v%. The content of the component (C) is suitable from the viewpoint of the effect of controlling the adsorption rate to the eye cells or relieving the discomfort of the eye.

Component (D) The ophthalmic composition according to the present embodiment may further contain a component (D) described below. The component (D) is at least one selected from the group consisting of taurine, propylene glycol, benzalkonium chloride, sorbic acid and salts thereof, polyoxyethylene hydrogenated castor oil, trometamol, and epsilon-aminocaproic acid. As the component (D), one type may be used alone, or two or more types may be used in arbitrary combination. By using the component (D) in combination, the effects of the present invention can be more remarkably exhibited. In particular, by using the component (D) together, the deterioration of the contact lens can be further suppressed. The details of the mechanism of controlling the adsorption rate to phospholipids by using the component (D) together have not been clarified, but by using the component (D) together, the micelle structure of the polysorbate 80 and the cooling agent is improved. It is also considered that it is slightly different and influences the affinity with phospholipids.

The component (D) used in the ophthalmic composition according to the present embodiment is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable.

The content of the component (D) used in the ophthalmic composition according to this embodiment is not particularly limited, and depends on the type of the component (D), the types and contents of the component (A) and the component (B) used in combination, and the like. Is set appropriately. The content of the component (D) is, for example, preferably 0.00005 to 10 w/v%, and more preferably 0.0001 to 8 w/v%, based on the total amount of the ophthalmic composition. It is more preferably 0.0005 to 6 w/v%, further preferably 0.001 to 5 w/v%. The content of the component (D) is suitable from the viewpoint of the effect of controlling the adsorption rate to eye cells or relieving the discomfort of the eye.

The ophthalmic composition according to this embodiment preferably further contains a buffer. With this, the pH of the ophthalmic composition can be adjusted, and the effects of the present invention can be more remarkably exhibited.

The buffer is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, tris buffer, aspartic acid, aspartate, edetate and the like. These buffers may be used alone or in any combination of two or more. Examples of the borate buffer include boric acid or salts thereof (alkali metal borate, alkaline earth metal borate, etc.). Examples of the phosphate buffer include phosphoric acid and salts thereof (alkali metal phosphate, alkaline earth metal phosphate, etc.). Examples of the carbonic acid buffer include carbonic acid or salts thereof (alkali metal carbonate, alkaline earth metal carbonate, etc.). Examples of the citric acid buffer include citric acid or salts thereof (alkali metal citrate, alkaline earth metal citrate, etc.). A borate or phosphate hydrate may be used as a borate buffer or a phosphate buffer. As a more specific example, boric acid or a salt thereof as a borate buffer (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.); phosphoric acid or a phosphoric acid buffer thereof as a phosphate buffer Salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.); Or a salt thereof (sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, etc.); as a citric acid buffer, citric acid or a salt thereof (sodium citrate, potassium citrate, calcium citrate, citric acid). Sodium dihydrogen acid, disodium citrate, etc.; Acetic acid or its salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.) as an acetic acid buffer; Aspartic acid or its salts (sodium aspartate, magnesium aspartate, Examples thereof include potassium aspartate). Among these buffers, borate buffers (for example, a combination of boric acid and borax, etc.) or phosphate buffers (for example, a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate, etc.) are preferable. Further, borate buffer is more preferable.

When a buffering agent is added to the ophthalmic composition according to the present embodiment, the content thereof includes the type of the buffering agent, the type and content of other compounding components, the use of the ophthalmic composition, the formulation form, the method of use, etc. It is set appropriately according to. As the content of the buffer, for example, based on the total amount of the ophthalmic composition, the total content of the buffer is preferably 0.001 to 15 w/v%, 0.01 to 10 w/v% Is more preferable, 0.05 to 7.5 w/v% is still more preferable, and 0.1 to 5 w/v% is particularly preferable.

The ophthalmic composition according to this embodiment preferably further contains a chelating agent. Thereby, the ophthalmic composition can be stably used for a long period of time, and the effect of the present invention can be more remarkably exhibited.

The chelating agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of the chelating agent include ethylenediaminediacetic acid (EDDA), ethylenediaminetriacetic acid, ethylenediaminetetraacetic acid (edetic acid, EDTA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), and diethylenetriaminepentaacetic acid (DTPA). Can be illustrated. Among these chelating agents, ethylenediaminetetraacetic acid is preferable. These chelating agents may be used alone or in any combination of two or more.

When compounding a chelating agent in the ophthalmic composition according to the present embodiment, the content, the type of chelating agent, the type and content of other compounding ingredients, the use of the ophthalmic composition, formulation form, method of use, etc. It is set as appropriate. As the content of the chelating agent, for example, based on the total amount of the ophthalmic composition, the total content of the chelating agent is preferably 0.0001 to 2 w/v%, and 0.0004 to 1.5 w/v. % Is more preferable, 0.0008 to 1 w/v% is further preferable, and 0.001 to 0.8 w/v% is particularly preferable.

The pH of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable range. The pH of the ophthalmic composition is in the range of 4.0 to 9.5, preferably 4.5 to 9.0, and more preferably 5.0 to 8.5. When the pH is within the above range, there is less irritation to the eye when the ophthalmic composition is used, the adsorption rate to eye cells is further controlled, and the discomfort of the eye tends to be alleviated.

The ophthalmic composition according to this embodiment preferably further contains a tonicity agent. With this, the osmotic pressure of the ophthalmic composition can be adjusted, and the effects of the present invention can be more remarkably exhibited. The isotonicity agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of the isotonicity agent include disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, carbonic acid. Examples thereof include sodium, sodium thiosulfate, polyethylene glycol, glucose, sorbitol and the like. Among these tonicity agents, polyethylene glycol, glucose, sodium chloride, potassium chloride or magnesium chloride is preferable, sodium chloride, potassium chloride or polyethylene glycol is more preferable, and sodium chloride is particularly preferable. These tonicity agents may be used alone or in any combination of two or more.

When the ophthalmic composition according to the present embodiment contains a tonicity agent, the content thereof is appropriately set according to the type of the tonicity agent, the type and content of the other contained components, and the like. As the content of the tonicity agent, for example, the total content of the tonicity agent is preferably 0.001 to 10 w/v%, and 0.01 to 5 w, based on the total amount of the ophthalmic composition. /V% is more preferable, and 0.05 to 3 w/v% is even more preferable.

The osmotic pressure of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within a range that is acceptable for the living body. The osmotic pressure ratio of the ophthalmic composition is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and further preferably 0.7 to 2.0. It is particularly preferably 0.8 to 1.6. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt, polyhydric alcohol, sugar alcohol or sugar. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9 w/v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia, and the osmotic pressure is the osmotic pressure measurement method described in the Japanese Pharmacopoeia. (Freezing point depression method) In addition, about the osmotic pressure ratio measurement standard solution (0.9 w/v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, it is in a desiccator (silica gel). It is allowed to cool, and 0.900 g thereof is accurately weighed, dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w/v% sodium chloride aqueous solution) can be used. ..

The ophthalmic composition according to the present embodiment preferably further contains a thickening agent. With this, the viscosity of the ophthalmic composition can be adjusted, and the effects of the present invention can be more remarkably exhibited.

Examples of the thickener include polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, cellulose derivative [methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxy. Methylcellulose, carboxyethylcellulose, nitrocellulose or salts thereof, etc.], polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 1500, Macrogol 4000, Macrogol 6000, etc.), sodium chondroitin sulfate, sodium hyaluronate, gum arabic, Examples thereof include gellan gum, tragacanth, dextran (40, 70, etc.), glucose, sorbitol, etc., and preferably polyvinylpyrrolidone (K25, K30, K90), carboxyvinyl polymer, cellulose derivative [methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl]. Methyl cellulose (2208, 2906, 2910), carboxymethyl cellulose or salts thereof, etc.], polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000, etc.) or dextran (70), more preferably polyvinyl. Pyrrolidone (K25, K30, K90), carboxyvinyl polymer, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910), carboxymethylcellulose or a salt thereof, polyethylene glycol (Macrogol 300, Macrogol 400, Macrogol 4000, Macrogol 6000) or dextran (70). From the viewpoint of the effect of controlling the adsorption rate to the eye cells or alleviating the discomfort of the eye, polyvinylpyrrolidone, hydroxyethylcellulose or hydroxypropylmethylcellulose are more preferable, and hydroxypropylmethylcellulose is particularly preferable. These thickeners may be used alone or in any combination of two or more.

When the ophthalmic composition according to the present embodiment contains a viscous agent, the content thereof is appropriately set according to the type of viscous agent, the type and content of other contained components, and the like. As the content of the viscous agent, for example, based on the total amount of the ophthalmic composition, the total content of the viscous agent is preferably 0.0001 to 8 w/v%, and 0.0005 to 5 w/v. % Is more preferable, 0.001 to 4 w/v% is further preferable, and 0.01 to 3 w/v% is particularly preferable.

The viscosity of the ophthalmic composition according to the present embodiment is not particularly limited as long as it is within the range that is acceptable to the living body. The viscosity at 25° C. measured by a rotational viscometer (RE550 viscometer, manufactured by Toki Sangyo Co., Ltd., rotor: 1°34′xR24) is preferably 0.1 to 1000 mPa·s, for example, 0.5 It is more preferably ˜100 mPa·s, and even more preferably 1-50 mPa·s.

The ophthalmic composition according to the present embodiment may contain a suitable amount of various pharmacologically active ingredients or physiologically active ingredients in combination with the above-mentioned components, as long as the effects of the present invention are not impaired. Such ingredients are not particularly limited, and examples thereof include active ingredients in various medicines described in the OTC Pharmaceutical Manufacturing and Marketing Approval Standard 2012 version (supervised by the Regulatory Science Society of Japan). Specifically, the components used in the ophthalmic drug include the following components.
Anti-allergic agents: cromoglycate, amlexanox, ibudilast, suplatast, pemirolast potassium, tranilast, olopatadine hydrochloride, levocabastine hydrochloride, acitazanolast and the like.
Antihistamines: chlorpheniramine maleate, diphenhydramine hydrochloride, ketotifen fumarate, etc.
Vasoconstrictor (decongestant): tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, naphazoline hydrochloride, naphazoline nitrate, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride and dl-methylephedrine hydrochloride.
Anti-inflammatory agents: pranoprofen, glycyrrhizic acid, allantoin, berberine sulfate, berberine chloride, azulenesulfonic acid, zinc sulfate, zinc lactate, lysozyme, salicylic acid, tranexamic acid, licorice and salts thereof.
Ocular muscle regulating agents: For example, cholinesterase inhibitors having an active center similar to acetylcholine, specifically, neostigmine methylsulfate, tropicamide, heleniene, atropine sulfate and the like.
Bactericides: acrinol, cetylpyridinium, benzethonium chloride, chlorhexidine, polyhexamethylene biguanide and alkyldiaminoethylglycine hydrochloride.
Amino acids: glycine, alanine, γ-aminobutyric acid, aspartic acid, potassium L-aspartate, glutamic acid, arginine, lysine, chondroitin sulfate, sodium chondroitin sulfate, sodium hyaluronate and alginic acid.
Vitamins: Vitamin B ₁ , vitamin B ₂ (flavin adenine dinucleotide sodium), niacin (nicotinic acid and nicotinic acid amide), pantothenic acid, vitamin B ₆ (pyridoxine, pyridoxal and pyridoxamine), biotin, folic acid, vitamin B ₁₂ ( Cyanocobalamin, hydroxocobalamin, methylcobalamin and adenosylcobalamin), retinol acetate, retinol palmitate and tocopherol acetate.

The ophthalmic composition according to the present embodiment, as long as the effect of the present invention is not impaired, according to the application or formulation form, according to a conventional method, various additives are appropriately selected, and one or more kinds thereof are selected. May be used in combination and may be contained in an appropriate amount. Examples of such additives include various additives described in Encyclopedia of Pharmaceutical Additives 2007 (edited by Japan Pharmaceutical Additives Association). The following additives are listed as typical components.
Carrier: For example, an aqueous carrier such as water or hydrous ethanol.
Sugars: For example, glucose, cyclodextrin and the like.
Sugar alcohols: for example, xylitol, sorbitol and the like. These may be d-form, l-form or dl-form.
Nonionic surfactants: POE(20) sorbitan monouranate (polysorbate 20), POE(20) sorbitan monopalmitate (polysorbate 40), POE(20) sorbitan monostearate (polysorbate 60) and POE tristearate (POE(20)). 20) POE sorbitan fatty acid ester such as sorbitan (polysorbate 65); POE (10) castor oil (polyoxyethylene castor oil 10) and POE (35) castor oil (polyoxyethylene castor oil 35) and other POE castor oil; POE (9) POE alkyl ether such as lauryl ether; POE (20) POP (4) POE-POP alkyl ether such as cetyl ether; POE (54) POP (39) glycol, POE (120) POP (40) glycol, POE (160) POP (30) glycol, POE (196) POP (67) glycol (Poloxamer 407, Pluronic F127) and POE (200) POP (70) glycol, and other polyoxyethylene/polyoxypropylene block copolymers; polyoxyl stearate Polyethylene glycol monostearate such as 40. In the compounds exemplified above, the number in parentheses indicates the number of added moles.
Amphoteric surfactants: N-[2-[[2-(alkylamino)ethyl]amino]ethyl]glycine and salts thereof (also called alkyldiaminoethylglycine or alkylpolyaminoethylglycine) and the like.
Negative ion surfactants: alkylbenzene sulfonate, alkyl sulfate, polyoxyethylene alkyl sulfate, α-sulfo fatty acid ester salt, α-olefin sulfonic acid and the like.
Positive ion surfactant: benzethonium chloride, etc.
Preservatives, fungicides or antibacterial agents: for example, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, Propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, polyhexanide hydrochloride, etc.), Glowkill (trade name, manufactured by Rhodia), etc.
Stabilizer: sodium formaldehyde sulfoxylate (Rongalit), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, dibutylhydroxytoluene, sodium edetate, etc.
Base: For example, octyldodecanol, titanium oxide, potassium bromide, paraffin, plastibase, lanolin and the like.

The ophthalmic composition according to the present embodiment is prepared by adding the above-mentioned components (A) and (B) and, if necessary, other components to the carrier so as to have a desired content. Specifically, for example, it can be prepared by dissolving or suspending the above components with purified water, adjusting to a predetermined pH and osmotic pressure, and sterilizing by filtration sterilization or the like.

The water content in the ophthalmic composition according to the present embodiment is preferably 85 w/v% or more, more preferably 90 w/v% or more, and more preferably 92 w/v with respect to the total amount of the ophthalmic composition. % Or more, more preferably 94 w/v% or more, still more preferably 96 w/v% or more. As water used in the ophthalmic composition, water that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable may be used, and as such water, specifically, distilled water, Examples include water, purified water, sterilized purified water, water for injection, distilled water for injection and the like.

The ophthalmic composition according to the present embodiment is provided by being contained in any container. The container for storing the ophthalmic composition is not particularly limited, and may be, for example, glass or plastic. It is preferably made of plastic. As the plastic, for example, polyethylene terephthalate, polyarylate, polyethylene naphthalate, polycarbonate, polyethylene, polytetrafluoroethylene, polypropylene, polybutylene terephthalate, polyimide, polymethylpentene and a copolymer of these constituent monomers, and these Examples include a mixture of two or more including materials. Preferred is polyethylene terephthalate. Further, the container for containing the ophthalmic composition may be a transparent container in which the inside of the container can be visually recognized, or an opaque container in which the inside of the container is difficult to be visually recognized. A transparent container is preferable. Here, the "transparent container" includes both a colorless transparent container and a colored transparent container. The ophthalmic composition may be contained and used in a multi-dose form that can be repeatedly used, for example, in a colored and transparent plastic container or the like, or may be contained and used in a single-use form.

The ophthalmic composition according to the present embodiment can be used as a drug or a quasi drug formulation, and is a so-called eye drop [however, the eye drop includes an eye drop capable of being instilled during contact lens wearing. In addition to artificial tears and eyewashes, the eyewashes include eyewashes that can be washed while wearing contact lenses. ], contact lens composition [contact lens mounting solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaning agent, contact lens cleaning preservative), etc.] .. Suitable examples of the present invention include eye drops, artificial tears, eye washes, and contact lens mounting liquids, and particularly preferable examples include eye drops and artificial tears. When the ophthalmic composition is used as a composition for contact lenses, it can be applied to all contact lenses including hard contact lenses and soft contact lenses, and can also be applied to the contact lenses in a worn state. It is possible. The ophthalmic composition according to the present embodiment is suitable for application to contact lenses also from the viewpoint of the effect of controlling the adsorption rate to eye cells due to the load on the eye cells by wearing contact lenses or alleviating the discomfort of the eye. Is.

The above ophthalmic composition can be applied to any contact lens as long as it is a known contact lens. From the viewpoint that the diameter of the lens is large and the contact area with the eye is large, it is particularly preferably applied to a soft contact lens. Soft contact lenses (SCL) are classified by the method described in ISO18369-1:2006 and ISO18369-1:AMENDMENT1, for example.

The ophthalmic composition according to the present embodiment can not only improve the symptom itself but also control the adsorption rate to mucosal cells in order to alleviate eye irritation or toxicity. Symptoms include, for example, subjective symptoms of the eyes that are tingling or tingling (uncomfortable feeling, irritation) as well as subconscious symptoms, which may be caused by dry eyes, use of contact lenses, or allergic conjunctivitis. is there. The ophthalmic composition according to this embodiment can be applied for the purpose of prevention, improvement or treatment of various symptoms. From the viewpoint of being able to control eye irritation or toxicity, it is suitable for discomfort caused by allergic conjunctivitis, contact lens wear, dry eyes, and the like. That is, the ophthalmic composition is preferably used as a discomfort reducing agent. In other words, the discomfort reducing agent contains the ophthalmic composition.

From another perspective, the ophthalmic composition according to the present embodiment can also sustain the aroma of the cooling agent contained in the ophthalmic composition, and thus is suitably used as an aroma sustaining agent for an ophthalmic composition. ..

From another viewpoint, the ophthalmic composition according to the present embodiment can also suppress the deterioration of the contact lens, and thus is preferably used as a deterioration suppressing agent for soft contact lenses.

(Method of giving discomfort alleviation effect)
In another embodiment of the present invention, the ophthalmic composition is provided with (A) polysorbate 80 and (B) a cooling agent to impart an ocular discomfort-alleviating action to the ophthalmic composition. How to do
There is provided a method, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity of 1.27 to 1.63.
In yet another embodiment of the invention, an eye by application of an ophthalmic composition comprising the step of applying to the eye an ophthalmic composition containing (A) polysorbate 80 and (B) a cooling agent. A method of relieving the discomfort of
There is provided a method, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity of 1.27 to 1.63.

According to the ophthalmic composition according to the present embodiment, the polysorbate 80 having a polydispersity of 1.27 to 1.63 in the ophthalmic composition and a cooling agent are combined to increase the adsorption rate to eye cells. By controlling, it is possible to further alleviate the discomfort of the eye.

(Method of imparting action to maintain aromaticity)
In another embodiment of the present invention, the ophthalmic composition comprises: (A) polysorbate 80; and (B) a cooling agent, wherein the ophthalmic composition retains the aromaticity of the cooling agent. A method of imparting the action of
There is provided a method, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity of 1.27 to 1.63.
In another embodiment of the present invention, the aroma of the refreshing agent contained in the ophthalmic composition is obtained by adding (A) polysorbate 80 and (B) a refreshing agent to the ophthalmic composition. A way to sustain sex,
There is provided a method, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity of 1.27 to 1.63.

According to the ophthalmic composition according to the present embodiment, by combining the polysorbate 80 having a polydispersity of 1.27 to 1.63 in the ophthalmic composition and a cooling agent, a cooling agent contained in the ophthalmic composition. It is possible to maintain the fragrance of the agent.

(Method of giving an action of suppressing deterioration of soft contact lens)
In another embodiment of the present invention, an effect of suppressing deterioration of a soft contact lens in the ophthalmic composition, which comprises adding (A) polysorbate 80 and (B) a cooling agent to the ophthalmic composition. Is a method of giving
There is provided a method, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity of 1.27 to 1.63.
In yet another embodiment of the present invention, an ophthalmic composition comprising the step of contacting a soft contact lens with an ophthalmic composition containing (A) polysorbate 80 and (B) a cooling agent. A method for suppressing the deterioration of soft contact lenses,
There is provided a method, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity of 1.27 to 1.63. Here, "the step of bringing the ophthalmic composition into contact with the soft contact lens" includes, for example, storing the soft contact lens in a storage solution, washing the soft contact lens with a cleaning solution, and instilling the soft contact lens during wearing. Applying the agent to the eye can be mentioned.

According to the ophthalmic composition according to the present embodiment, polysorbate 80 having a polydispersity of 1.27 to 1.63 in the ophthalmic composition and a cooling agent are combined to suppress deterioration of the soft contact lens. It is possible to

(Production method)
In the production of the ophthalmic composition according to the present embodiment, the polysorbate 80 having a polydispersity of 1.27 to 1.63 and a cooling agent are blended in the ophthalmic composition to obtain an adsorption rate to eye cells. It is suggested that the control effect (control action) of the above can contribute to the provision of a formulation having maintained or improved.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Test Example 1. Measurement of Adsorption Rate to Phospholipid (1) Test Method Using polysorbate 80 having different polydispersities shown in Table 1, test solution A (which is an ophthalmic composition shown in Tables 2 and 3) Comparative Example 1-A, Comparative Example 2-A, Example 1-A, Example 2-A, Example 3-A) and Test Liquid B (Comparative Example 1-B, Comparative Example 2-B, Example 1) -B, Example 2-B, Example 3-B) were prepared, and the polydispersity of polysorbate 80 in each test solution was measured. Next, a QCM (Quartz Crystal Microbalance) device was used to measure in real time the frequency that fluctuates depending on the amount of each test solution adsorbed to the phospholipid immobilized on the quartz sensor. Then, using the adsorption rate constants of the test solutions A and B having the corresponding numbers, the rate of inhibition of the adsorption rate was calculated based on the equation 1 described later. The test liquids A and B having corresponding numbers are, for example, Comparative Example 1-A and Comparative Example 1-B.

Biomolecule Interaction Quantitative QCM Device AFFINIX Q (manufactured by Initiam Co., Ltd.) was charged with a stirrer and 7 mL of PBS (Kojin Bio Co., Ltd.) in a glass cell. The glass cell was set in a QCM device. The temperature was kept constant at 25° C. and the stirring speed was 1000 rpm. Next, the phospholipid was fixed to the crystal sensor. Specifically, a cotton swab containing a 1% SDS aqueous solution was used to scrub the gold electrodes of the crystal sensor so as not to scratch them, and then rinsed with ultrapure water. Then, 5 μL of a piranha solution prepared by mixing concentrated sulfuric acid:30% hydrogen peroxide water at a ratio of 3:1 was added to the electrode portion, and the mixture was allowed to stand for 5 minutes. The piranha solution was rinsed with ultrapure water, and the water remaining on the electrode surface was removed by blowing air. The crystal sensor was attached to the QCM device, and it was allowed to stand until the average frequency was within the range of 27000000±100,000 Hz, and the average frequency shift per minute and the vibration width were both stable within 3 Hz. Next, the electrode was removed from the QCM device, and phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) (manufactured by Sigma) was dissolved in chloroform so as to be 1 mg/mL, and 2 μL was applied on the electrode. It was dropped and air dried. After confirming that the electrodes were dry, the bath was bathed at 60° C. for 30 minutes. After that, the excess phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) left unfixed on the electrode of the crystal sensor was washed with ultrapure water, and the water around the electrode was washed with paper. It was removed with a waste cloth. The crystal sensor thus fixed with phospholipids was set in a QCM device and submerged in a glass cell containing PBS. Waiting for the frequency to stabilize, the frequency at that time was taken as the initial value. Next, 7 μL of the test solution was added to the glass cell, and the fluctuating frequency was monitored by the adsorption behavior of the test solution with respect to the phospholipid on the quartz sensor. Monitoring continued until the frequency stabilized.

From the initial value, select the frequency up to 1 minute after adding the test solution, and use the analysis software AQUA (Initial Co., Ltd.) to perform fitting to an exponential function to obtain the apparent adsorption rate constant K _obs . It was calculated. Further, when the drift (slope) appeared constant in the frequency after fixation on the phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) crystal sensor, slope correction was performed.

From the obtained K _obs , the suppression rate of the adsorption rate was calculated based on the equation (1). The suppression rate is the rate of reduction.
Inhibition rate of adsorption rate (%)=[{(K _{obs of} test liquid containing no cooling agent)-(K _{obs of} test liquid containing cooling agent)}/(of the test liquid containing a cooling agent K _obs )]×100 (Equation 1)

(2) Test results The results are shown in Table 4. By combining the various components (A) having different polydispersities and the component (B), the effect of suppressing the adsorption rate is reduced in the component (A) having a polydispersity of 1.21 or less in the test solution. (Comparative Examples 1-2), it was shown that the effect of suppressing the adsorption rate was improved in the component (A) having a polydispersity of 1.27 or more in the test liquid (Examples 1-3).

Test example 2. Sensory test (1)
(1) Test method Each test solution as an ophthalmic composition was prepared according to a conventional method according to Tables 5 and 6 below, and the polydispersity of polysorbate 80 in each test solution was measured. 9 mL of each test solution was filled in a 10 mL capacity transparent glass vial (septum cap). The heat treatment was performed by leaving it in a constant temperature bath at 60° C. for 24 hours. 30 μL of each test solution immediately after preparation and each test solution after heat treatment were dropped on the arm, spread with a finger in a circular shape having a diameter of about 2 cm, and smelled, and evaluated by the VAS (Visual Analog Scale) method. In other words, regarding "fresh scent" and "good scent", "not felt at all" was set to 0 mm and "very felt" was set to 100 mm at both ends of a straight line of 10 cm and corresponded to the size of each test solution. The subject was made to show one point on the straight line. The distance (mm) from the 0 mm point was measured and used as the sensory score. Scent-sensitive test subjects were selected and performed by 5 people, and the average score was calculated.

(2) Test Results Table 5 shows the average value of the fragrance scores of the test solutions immediately after preparation, and Table 6 shows the average value of the fragrance scores of the test solutions after the heat treatment. A test solution 2-2 containing (A) polysorbate 80 and (B) 1-menthol, d-camphor or d-borneol, wherein the polydispersity of polysorbate 80 in the test solution is 1.27 to 1.34, 2-3, 2-5, 2-6, 2-8, 2-10 are test solutions 2-1, 2-4, 2- in which the polydispersity of polysorbate 80 in the test solution is less than 1.27. It was confirmed that, as compared with Nos. 7 and 2-9, a significantly higher aromaticity was exhibited immediately after preparation. Further, the test solution after the heat treatment also contains (A) polysorbate 80 and (B) 1-menthol, d-camphor or d-borneol, and the polydispersity of polysorbate 80 in the test solution is from 1.27 to 1. The test solutions 2-2, 2-3, 2-5, 2-6, 2-8, 2-10, 2-11 and 2-12, which are 63, have a polydispersity of 1 in the test solution. Compared with the test liquids 2-1, 2-4, 2-7, and 2-9, which are less than 0.27, they show a significantly higher fragrance, so that the fragrance can be maintained even during long-term use or storage of the ophthalmic composition. It was confirmed that sex continued.

Test example 3. Sensory test (2)
(1) Test method Evaluation of aromaticity after heat treatment was carried out in the same manner as in Test Example 2 except that each test solution as an ophthalmic composition was prepared according to a conventional method according to Tables 7 and 8 below. I went. Scent-sensitive test subjects were selected and performed by 5 people, and the average score was calculated.

(2) Test results Tables 7, 8 and 9 show the average values of the fragrance scores. (A) Polysorbate 80, (B) A cooling agent (l-menthol) are contained, and the polydispersity degree of the polysorbate 80 in the test liquid is 1.34 compared with the test liquid 2-3 which is (A) polysorbate 80. , (B) a cooling agent (l-menthol) and (C) polyvinyl alcohol, glycerin, panthenol, sulfamethoxazole, calcium chloride, magnesium sulfate, sodium hydrogen carbonate or D-mannitol, in a test solution. The test solutions 3-1 to 3-8 in which the polydispersity of polysorbate 80 is 1.34 show remarkably high aromaticity after heat treatment. Therefore, during the long-term use or storage of the ophthalmic composition, the aromaticity is high. It was confirmed to last. Further, a test liquid 2-5, which contains (A) polysorbate 80, (B) a cooling agent (d-borneol), and whose polydispersity of polysorbate 80 in the test liquid is 1.27 to 1.34. Compared with -6, (A) polysorbate 80, (B) a cooling agent (d-borneol) and (C) polyvinyl alcohol or glycerin are contained, and the polydispersity of polysorbate 80 in the test solution is 1.27 to 1. Since the test liquids 3-9 to 3-12 of 0.34 exhibit remarkably high fragrance after heat treatment, it was confirmed that the fragrance persists during long-term use or storage of the ophthalmic composition. Further, a test liquid 2-10 or 2 containing a polysorbate 80 (A) and a cooling agent (d-camphor) (B), wherein the polydispersity of the polysorbate 80 in the test liquid is 1.27 to 1.34. Compared with -11, (A) polysorbate 80, (B) a cooling agent (d-camphor) and (C) glycerin were contained, and the polydispersity of polysorbate 80 in the test solution was 1.27 to 1.34. Since the certain test liquids 3-14 and 3-15 exhibit remarkably high aromaticity after heat treatment, it was confirmed that the aromaticity persists during long-term use or storage of the ophthalmic composition. Further, compared with the test liquid 2-1 which contains (A) polysorbate 80, (B) a cooling agent (d-borneol), and the polydispersity of polysorbate 80 in the test liquid is 1.19, (A) Test liquid 3-13, which contained polysorbate 80, (B) a cooling agent (d-borneol) and (C) polyvinyl alcohol, and whose polydispersity of polysorbate 80 in the test liquid was 1.19 was aroma after heat treatment. The sex has decreased.

Test example 4. Evaluation of contact lenses (1)
(1) Test method Each test solution was prepared according to the conventional method according to Tables 10 and 11 below, and the polydispersity of polysorbate 80 in each test solution was measured.
Each soft contact lens (USAN name: Etafilcon A; water content 58.0%, POWER-3.00, B.C.8.5, DIA 14.2 mm) was immersed in 10 mL of physiological saline solution, and one piece each was immersed for 4 hours or more. It was left still at 25°C. 5 mL of each test solution was filled in a transparent glass vial (septum cap) having a capacity of 10 mL, and one soft contact lens treated with a physiological saline solution was immersed therein. The heat treatment was carried out by leaving it at 25° C. for 24 hours or 60° C. for 24 hours in a constant temperature bath. After the heat treatment, the glass vial was allowed to stand at room temperature for 1 hour to bring the test solution and the contact lens to the same temperature as room temperature. The contact lens was taken out from the glass vial, the water was wiped off, and the convex shape was faced downward and gently placed on a graduated slide glass. At this time, care was taken so that the contact surface between the contact lens and the slide glass was a circular shape without distortion. Five seconds after the installation, the diameter of the tangent circle was measured with a microscope. Immediately thereafter, the contact lens was put back into the test solution in the heat-treated glass vial. In order to avoid drying of the contact lens, it was promptly taken out from the glass vial until the measurement. Three contact lenses were used for one test solution, and one contact lens was measured three times to calculate an average value.

Under the same test conditions, the contact lens was immersed in a physiological saline solution (sodium chloride 0.9 w/v%, pH 7.0), the diameter of the contact surface circle between the contact lens and the slide glass was measured, and the average value was calculated. .. The average value after treatment with physiological saline solution and the average value after immersion in each test solution subjected to heat treatment at 25° C. or 60° C. were applied to the following formula 2 to calculate the alteration rate of the soft contact lens. Deterioration of the soft contact lens is a change in diameter of a contact surface circle between the soft contact lens and the slide glass. That is, the closer the absolute value of the alteration rate is to 0, the smaller the alteration. Deterioration rate (%)=[{(diameter of surface circle after treatment with physiological saline)-(diameter of surface circle after treatment with test solution)}/diameter of surface circle after treatment with physiological saline]×100 (Formula 2)

(2) Test results The results are shown in Tables 10 and 11. A test solution 4-2 containing (A) polysorbate 80 and (B) 1-menthol, d-camphor or d-borneol, and having a polydispersity of polysorbate 80 in the test solution of 1.27 to 1.63. 4-3, 4-4, 4-6, 4-7, 4-8, 4-10 and 4-11 have test solutions 4-1, 4-5 and 4- having polydispersity of 1.19. It was confirmed that the absolute value of the alteration rate was smaller than that of No. 9. That is, it was found that the test solution in which the polydispersity of the polysorbate 80 in the test solution was 1.27 to 1.63 suppressed the deterioration of the contact lens at 25°C. Further, test solutions 4-13, 4-14, 4-containing (A) polysorbate 80 and (B) d-camphor and having a polydispersity of polysorbate 80 in the test solution of 1.27 to 1.63. It was confirmed that Sample No. 15 has a smaller absolute value of the alteration rate after the treatment at 60° C. than that of Test Solution 4-12 having a polydispersity of 1.19. That is, it was found that the test solution in which the polydispersity of polysorbate 80 in the test solution was 1.27 to 1.63 suppressed the deterioration of the contact lens even after the heat treatment. Therefore, it was found that deterioration of contact lenses is suppressed even during long-term use or storage.

Test example 5. Evaluation of contact lenses (2)
(1) Test method A contact lens was evaluated in the same manner as in Test Example 4 except that each test solution was prepared according to the conventional method according to Table 12 below.

(2) Test results The results are shown in Table 12. Contains (A) polysorbate 80, (B) cooling agent (l-menthol) and (D) taurine, propylene glycol, benzalkonium chloride, potassium sorbate, polyoxyethylene hydrogenated castor oil, trometamol or epsilon-aminocaproic acid However, the test solutions 5-1, 5-2, 5-3, 5-4, 5-5, and 5-6 in which the polydispersity of the polysorbate 80 in the test solution is 1.34 are (A) polysorbate 80. , (B) a cooling agent (1-menthol), and the polydispersity of polysorbate 80 in the test solution was 1.34, as compared with test solution 4-3, the absolute rate of alteration after treatment at 60° C. was absolute. It was confirmed that the value was small. That is, it was found that deterioration of contact lenses was suppressed even during long-term use or storage. A test in which (A) polysorbate 80, (B) a cooling agent (1-menthol) and (D) trometamol or epsilon-aminocaproic acid are contained, and the polydispersity of polysorbate 80 in the test solution is 1.63. Liquids 5-7 and 5-8 contain (A) polysorbate 80, (B) cooling agent (l-menthol), and polysorbate 80 in the test liquid has a polydispersity of 1.63. It was confirmed that the absolute value of the alteration rate after the treatment at 60°C was smaller than that of -4. That is, it was found that deterioration of contact lenses was suppressed even during long-term use or storage.

Claims (1)

Polysorbate 80,
A cooling agent,
An ophthalmic composition containing:
An ophthalmic composition, wherein the polysorbate 80 in the ophthalmic composition has a polydispersity index (M _z /M _w ) of 1.27 to 1.63.